Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives

Definitions

• Cholecystokinins (CCK) and gastrin are structurally-related neuropeptides which exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., p. 169 and G. Nisson, ibid, p. 127).
• the predominant fragments are the carboxy terminal octapeptide, H-Asp-Tyr(S0 3 H)-Met-Gly-Trp-Met-Asp-Phe-NH 2 (CCK-8s, CCK 26 - 33 ) and tetrapeptide, CCK-4 (CCk 30-33 ).
• the carboxy terminal octapeptide possesses the full biological profile of CCK, Dockray, G.J. et al., "Isolation, Structure and Biological Activity of Two Cholecystokinin Octapeptides from Sheep Brain", Nature 274, 711 (1978), and meets many anatomical and biochemical criteria which characterize a neurotransmitter, Vanderhaeghen, J.J. et a l ., "J. Neuronal Cholecystokinin", Ann. N.Y Acad. Sci., 448, (1985).
• the presence of high concentrations of CCK-8s in the mammalian CNS is complemented with findings of specific and high affinity membrane-bound CCK binding sites, Innis, R.B. et a l ., "Distinct Cholecystokinin Receptors in Brain and Pancreas", Proc. Natl. Acad. Sci. U.S.A., 77, 6917 (19
• CCK receptors have been differentiated into primarily two subtypes based on their affinity for CCK fragments and analogues, Innis, R.B. et al., "Distinct Cholecystokinin Receptors in Brain and Pancreas", Proc. Natl. Acad. Sci. U.S.A., 77,6917 (1980) .
• CCK receptors have been differentiated into primarily two subtypes based on their affinity for CCK fragments and analogues, Innis, R.B. et al., “Distinct Cholecystokinin Receptors in Brain and Pancreas", Proc. Natl. Acad. Sci.
• CCK-A receptors previously known as peripheral CCK receptors, are located in organs such as the pancreas, gallbladder, and colon. They exhibit high affinity for CCK-8s and a lower affinity for the corresponding desulphated fragment, CCK-8d, for CCK-4, and gastrin. Recent autoradiographic results have localized CCK-A receptors in the brain as well, Hill, D.R. et al., "Autoradiographic Localization and Biochemical Characterization of Peripheral Type CCK Receptors in Rat CNS Using Highly Selective Nonpeptide CCKAntagonists", J. Neurosci., 7, 2967 (1987).
• CCK-B receptors are widely distributed throughout the brain and display high affinity for CCK-8s, CCK-4, and pentagastrin, Hill, D.R. et al., "Autoradiographic Localization and Biochemical Characterization of Peripheral Type CCK Receptors in Rat CNS Using Highly Selective Nonpeptide CCK Antagonists", J. Neurosci, 7, 2967 (1987).
• CCK receptor subtypes In addition to the above mentioned CCK receptor subtypes is a third type, the stomach gastrin receptor, which appears to be closely related to the CCK-B receptor subtype, Beinfeld, M.C., "Cholecystokinin in the Central Nervous System; a Minireview", Neuropeptides, 3, 4111 (1983).
• the minimum fully potent CCK sequence at this receptor is CCK-4, Gregory, R.A., "A Review of some Recent Development in the Chemistry of the Gas- trins", Biorg. Chem., 8,497 (1979).
• CCK-A antagonists retain considerable therapeutic potential, Gertz, B.J., "Potential Clinical Applications, of a CCK Antagonist in Cholecystokinin Antagonists," Alan R. Liss, Inc.: New York, pp. 327 (1988).
• CCK-8s has a half-life of less than 1 hour
• Deschodt-Lanckman, K., et al. "Degradation of Cholecystokinin-like Peptides by a Crude Rat Brain Synaptosomal Fraction: a Study by High Pressure Liquid Chromatography", Reg. Pept., 2, 15(1981)
• implicit in the development of candidates for clinical use are criteria of high potency, selectivity, long in-vivo duration, oral bioavailability, and capability of penetrating the blood- brain barrier.
• compositions containing the compounds of Formula I which are useful in the treatment of panic disorder or anxiety disorder in a mammal, especially a human.
• the compounds of Formula I are also useful in the treatment of oncologic disorders, controlling pupil constriction in the eye, treating pain or inducing analgesia, or treating a withdrawal response produced by chronic treatment or abuse of drugs or alcohol .
• the present invention is directed to pharmaceutical compositions containing aromatic 1,4-benzodiazepines with fused 5- and 6-membered heterocyclic rings which are useful in the treatment of panic disorder or anxiety disorder in a mammal, especially a human.
• the compounds of Formula I are also useful in the treatment of oncologic disorders, controlling pupil constriction in the eye, treating pain or inducing analgesia, or treating a withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
• compositions of this invention contain 1,4-benzodiazepines with fused 5-and 6-membered heterocyclic rings as set forth in Formula I: wherein
• each expression i.e., m, n, p, C 1 -C 4 -alkyl, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
• CCK-A-antagonism relates to D-tryptophan, where C 4 a and N 6 of Formula I (C 3 a and N 5 for 5-membered heterocycles) correspond to the carbonyl carbon and a-amino nitrogen, respectively, of D-tryptophan and R 3 occupies the position of the indolylmethyl side chain.
• the preferred stereochemistry for CCK-B or gastrin antagonism may be either D or L depending on the nature of R 3 .
• R 3 (CH 2 ) n R 7 or the preferred stereochemistry corresponds to D-tryptophan, as above.
• the preferred stereochemistry corresponds to L-tryptophan.
• halo is F, CI, Br, or and C 1 -C 4 -alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.
• Preferred compounds according to the present invention include those wherein R 1 is H or methyl; R 2 is phenyl or o-F-phenyl; R 3 is or R 7 is or X 1 is H; X 2 is H, -N0 2 , halo, methyl or methoxy; Y is absent and Z is CH 2 ; or Y is absent and Z is N; or Y is NR 1 and Z is CH 2 ; or Y is CH 2 and Z is CH 2 ; or Y is CH 2 and Z is N.
• preferred compounds include those wherein R 3 is R 7 is and the stereochemistry corresponds to L-tryptophan.
• preferred compounds include those wherein R 3 is R 7 is where X 2 is halo, and wherein R 3 is where R 7 is and the sterochemistry corresponds to D-tryptophan.
• Even more particularly preferred compounds include, for CCK-A antagonism:
• the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formula I formed, e.g., from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, pamoic, maleic, hydrox- ymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, isethionic, and the like.
• the compounds of Formula I are particularly distinguished from benzodiazepines of the prior art by the presence of 3-substituents. These Formula I compounds bind strongly to CCK-receptors, but only weakly to benzodiazepine-receptors, especially with the increasing size of the 3-substituent.
• benzodiazepine (13) is treated first with sodium methoxide and then with carbobenzoxybromoethyl- or propylamine to give (14).
• Compound (14) is then treated with a solution of HBr in glacial acetic acid to give the free amino derivative (15).
• the cyclodehydration product (16) is formed by heating (15) under reflux in ethanol.
• the hydroxy alkyl derivative (20) is generated by adding an aldehyde to a solution of (18).
• Treatment of (18) with an epoxide yields the hydroxyethyl derivative (19).
• By treating (18) with an alkyl halide the alkyl derivative (17) is produced.
• An alternative procedure for obtaining (17) is to treat the compounds from Scheme III with an alkyl halide and a strong base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and heating.
• DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
• Reaction Scheme Vl describes the formation of Formula I compounds where R 3 is a substituted amino moiety.
• the amino compounds (26) may be obtained by nitrosation of (18) followed by reduction of the oxime (25) with Raney nickel and hydrogen.
• Compound (26) may also be treated with an N-protected a-amino acid and a coupling reagent such as DCC or DPPA (diphenylphosphorylazide) to give the amides of structures (27).
• a coupling reagent such as DCC or DPPA (diphenylphosphorylazide)
• the pharmaceutically-acceptable salts of the compounds of present invention may be synthesized from the compounds of Formula I which contains a basic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base with stoichiometric amounts of or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or in various combinations of solvents.
• Screening of the novel compounds according to the present invention to determine biological activity and obtain an IC 50 value for them, in order to identify significant CCK-antagonism, may be accomplished using 125 1-CCK-receptor binding assay and in vitro isolated tissue preparations.
• 125 1-gastrin and 3 H-pentagastrin binding assays are used. These tests involve the following:
• CCK-8 radiolabeled with 125 1-Bolton Hunter reagent (2000 Ci/mmole) is purchased from New England Nuclear (NEN) and receptor binding is performed according to Innis and Snyder (Proc. Natl. Acad. Sci., 77, 6917-6921, 1980) with minor modifications as described in Chang and Lotti (Proc. Natl. Acad. Sci. U.S.A, 83, 4923-4926, 1986).
• the whole pancreas of a male Sprague-Dawley rat (200-350 g), which has been sacrificed by decapitation, is dissected free of fat tissue and homogenized in 20 volumes of ice-cold 50 mm Tris HCI (pH 7.7 at 25°C) with a Brinkmann Polytron PT-10.
• the homogenates are centrifuged at 48,000 g for 10 minutes, then the resulting pellets are resuspended in Tris Buffer, centrifuged as above, and resuspended in 200 volumes of binding assay buffer (50 mm Tris HCI, pH 7.7 at 25°C, 5 mm dithiothreitol and 0.1 mm bacitracin).
• reaction mixtures are incubated at 37°C for 30 minutes and then filtered on glass fiber GF/B filters, which are then rapidly washed with 3 x 4 ml of ice cold Tris HCI containing 1 mg/ml BSA, and the filters are counted with a Beckman Gamma 5000.
• 125 1-CCK-8 is progressively diluted with increasing concentrations of CCK-8.
• 125 I-CCK-8 binding is performed similarily to the method described by Saito et al. (J. Neurochem., 37,483-490,1981), with modifications described by Chang and Lotti (Proc. Natl. Acad. Sci. USA, 83,4923-4926,1986).
• Tris HCI Tris HCI [pH 7.4 at 25°C].
• the cerebral cortex is dissected and used as a receptor source and each gram of fresh guinea pig brain tissue is homogenized in 10 ml of Tris/Trizma buffer with a Brinkmann polytron PT-10.
• binding assay buffer 10 mM N-2-hydroxy-ethyl-piperazine-N'-2-ethanesulfonic acid (HEPES), 5 mM MgCl 2 , 1 mM ethyleneglycol-bis-( ⁇ -aminoethyl-ether)-N,N'-tetraacetic acid (EGTA), 0.4% BSA (bovine serum albumin) and 0.25 mg/ml bacitracin, pH 6.5).
• HEPES N-2-hydroxy-ethyl-piperazine-N'-2-ethanesulfonic acid
• MgCl 2 5 mM MgCl 2
• EGTA ethyleneglycol-bis-( ⁇ -aminoethyl-ether)-N,N'-tetraacetic acid
• BSA bovine serum albumin
• the remainder of the binding assay method is as described for the pancreas method, except that the reaction mixtures are incubated at 25°C for 2 hours before centrifugation.
• the two halves of the gall bladders, free of adjacent tissue, of male Hartley guinea pigs (400-600g), which have been sacrificed by decapitation, are suspended under Ig tension along the axis of the bile duct in 5 ml organ bath, containing a Kreb's bicarbonate solution of 118 mm NaCI, 4.75 mm KGI, 2.54 mm CaCl 2 , 1.19 mm KH 2 PO 4 , 1.2 mm MgS0 4 , 25 mm NaHC0 3 and 11 mm dextrose, which is maintained at 32°C and bubbled with a mixture of 95% 0 2 and 5% CO 2 .
• the tissues are washed every 10 minutes for one hour to obtain equilibrium prior to the beginning of the study and the isometric contractions of the strips are recorded using Statham (60g:0.12 mm) strain gauges and a Hewlett-Packard 77588 recorder.
• CCK-8 is added cumulatively to the baths and EC 50 's are determined using regression analysis. Afterwash- out (every 10 minutes for one hour), the compound to be tested is added at least 5 minutes before the addition of CCK-8 and the EC 50 of CCK-8 in the presence of compound to be tested is similarly determined.
• a piece of approximately 2 cm is suspended in 5 ml organ bath containing Krebs solution and bubbled with 95% 0 2 and 5% C0 2 at 37°C under 0.5 g tension.
• CCK-8 is added cumulatively to the baths and EC 50 values in the presence and absence of compounds to be tested are determined, as described in the gall bladder protocol above.
• Guinea pig gastric mucosal glands are prepared by the procedure of Berglingh and Obrink, Acta Physiol. Scand. 96: 150 (1976), with a slight modification according to Praissman et al. C. J. Receptor Res. 3: (1983).
• Gastric mucosa from male Hartley guinea pigs (300-500 g body weight) are washed thoroughly and minced with fine scissors in standard buffer consisting of the following: 130 mm NaCI, 12 mm NaHC0 3 , 3 mm NaH 2 P0 4 , 3 mm Na 2 HP0 4 , 3 mm K 2 Hp0 4 , 2 mm MgS0 4 , 1 mm CaCl 2 , 5 mm glucose, 4 mm L-glutamine and 25 mm HERPES at pH 7.4.
• the minced tissues are washed and incubated in a 37°C shaker bath for 40 minutes, with the buffer containing 0.1% collagenase and 0.1% BSA, and bubbled with 95% 0 2 and 5% CO 2 .
• the tissues are passed twice through a 5 ml glass syringe to liberate the gastric glands, and then filtered through 200 mesh nylon.
• the filtered glands are centrifuged at 270 g for 5 minutes and washed twice by resuspension and centrifugation.
• the washed guinea pig gastric glands are resuspended in 25 ml of standard buffer containing 0.25 mg/ml of bacitracin.
• 10 ⁇ l of buffer (for total binding) or gastrin (1 ⁇ M final concentration, for nonspecific binding) or test compound and 10 ⁇ l of 125 1-gastrin (NEN, 2200 Ci/mmole, 25 pM final) or 3 H-pentagastrin (NEN 22 Ci/mmole, 1 nM final) are added to 220 ⁇ l of gastric glands in triplicate tubes which are aerated with 95% 0 2 and 5% CO 2 and capped.
• reaction mixtures after incubation at 25°C for 30 minutes, are filtered under reduced pressure on glass G/F B filters (Whatman) and immediately washed with 4 x 4 ml of standard buffer containing 0.1% BSA.
• the radioactivity on the filters is measured using a Beckman gamma 5500 for 125 1-gastrin or liquid scintillation counting for 3 H-pentagastrin.
• the compounds of Formula I may further be useful in the treatment or prevention of additional central nervous system disorders including neurological and pyschiatric disorders.
• additional central nervous system disorders include anxiety disorder and panic disorder.
• Additional examples of central nervous system disorders include panic syndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronic anxiety, and endogenous anxiety.
• the compounds of Formula I may further be useful in the treatment of oncologic disorders.
• oncologic disorders include small cell adenocarcinomas and primary tumors of the central nervous system glial and neuronal cells.
• adenocarcinomas and tumors include, but are not limited to, tumors of the lower esophagus, stomach, intestine, colon and lung, including small cell lung carcinoma.
• the compounds of Formula I may further be used to control pupil constriction in the eye.
• the compounds may be used for therapeutic purposes during eye examinations and intraocular surgery in order to prevent mio- sis.
• the compounds may further be used to inhibit moisis occurring in association with ulceris, uveitis and trauma.
• the compounds of Formula I are also useful for directly inducing analgesia, opiate or non-opiate mediated, as well as anesthesia or loss of the sensation of pain.
• the compounds of Formula I may further be useful for preventing or treating the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
• drugs include, but are not limited to cocaine, alcohol or nicotine.
• the compounds of the instant invention or pharmaceutically-acceptable salts thereof may be administered to a human subject either alone or, preferably, in combination with pharmaceutically-acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
• the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
• carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
• useful diluents include lactose and dried corn starch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
• sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
• the total concentration of solutes should be controlled in order to render the preparation isotonic.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
• an effective daily dosage will be in the range of from about 0.005 mg/kg to about 50 mg/kg of body weight, and preferably, of from about 0.05 mg/kg to about 50 mg/kg of body weight, and most preferably, of from about 0.5 mg/kg to about 20 mg/kg of body weight administered in single or divided doses.
• dosage levels outside these limits.
• doses as low as about 1 ng/kg, about 0.005 ⁇ g to about 0.05 f..lg, or about 100 ng to about 100 wg/kg may be administered.
• preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist maybe administered orally (p.o.), administered in single or divided doses per day (b.i.d.). Other routes of administration are also suitable.
• the effective dosage range is preferably from about 100 ng/kg to about 1 mg/kg by intraperitoneal administration.
• Oral administration is an alternative route, as well as others.
• This compound is prepared according to the method of Earley, et al., J. Med. Chem., 11, 774-777 (1968).
• a solution of 150 mL of methanol containing 5 g 2,4-dihydro-4-oximino-6-phenyl-IH-imidazo[1,2-a]-[1,4]-benzodiazepine is treated with a slurry of active Raney-nickel catalyst 1 in ethanol (10 g).
• the resulting suspension is hydrogenated on a Parr apparatus at 60 psi and 23°C for about 30 hours, and the catalyst is removed by filtration. The filtrate is concentrated to afford the title compound.
• the pH of the reaction mixture is adjusted to 8.5 with triethylamine, and after 1/2 hour, the DMF is removed in vacuo, and the residue partitioned between ethyl acetate and 10% citric acid solution (10 mL). The layers are separated and the organic phase is washed with sodium bicarbonate solution (NaHC0 3 , saturated). The combined organic layers are washed with brine, dried over Na 2 S0 4 , filtered, and evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
• Raney-Nickel catalyst is prepared according to Fieser & Fieser, Reagents for Organic Synthesis, Vol. I, John Wiley & Sons, Inc., New York 1967, p. 729.
• This compound is prepared according to the method of Example 1 using carbobenzoxypropylamine to furnish a fused 6-membered heterocycle rather than a 5-membered one.
• This compound is prepared according to the method of Example 2.
• This compound is prepared according to the method of Example 3 and resolved according to the methods of Examples 4 through 6.
• This compound is prepared according to the method of Example 8.
• This compound is prepared according to the methods of Muller and Strauss, Helv. Chim. Acta, 65, 2118-2132 (1982).
• This compound is prepared according to the method of Example 2 using lityium diisopropylamide in place of potassium tert-butoxide.
• This compound is prepared according to the method of Example 3, with the 2 diastereomers being separated chromatographically and resolved according to the methods of Examples 4 through 6.
• This compound (either configuration at position 3a) is prepared according to the method of Example 7.
• This compound (either configuration at position 3a) is prepared according to the method of Example 8.
• This compound is prepared according to the methods of Muller and Strauss, Helv. Chim, Acta, 65 2118-2132 (1982).
• This compound is prepared according to the method of Example 15.
• This compound is prepared according to the method of Example 3, with the diastereomers being separated chromatographically and resolved according to the methods of Examples 4 through 6.
• This compound (either configuration at position 4a) is prepared according to the method of Example 8.
• This compound (either configuration at position 4a) is prepared according to the method of Example 7.
• This compound is prepared according to the methods of Muller and Strauss, Helv. Chim. Acta, 65, 2118-2132 (1982), or Smith et al., J. Med. Chem, 23, 952-955 (1980).
• This compound is prepared according to the method of Example 15.
• This compound is prepared according to the method of Example 3 (either configuration at position 4a) and resolved according to the methods of Examples 4 through 6.
• This compound (either configuration at position 4a) is prepared according to the method of Example 7.
• This compound (either configuration at position 4a) is prepared according to the method of Example 8.

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